or 10 and 30 min (naked mole-rat) of anoxia
(Fig. 2A). In contrast to mice, only minor changes
in the succinate/fumarate ratio (16) were observed in naked mole-rat tissues during anoxia,
a sign of mitochondrial shutdown (fig. S6). GC-MS
metabolomics can resolve hexoses, which allowed
us to observe a specific and marked increase in
fructose and sucrose concentration in the liver,
kidney, and blood of naked mole-rats 10 min
into anoxia (Fig. 2, B to D, and fig. S7, A and B).

No statistically significant changes in the levels ofthese sugars were seen in mouse tissues duringanoxia (Fig. 2D and fig. S7). The unexpected ap-pearance of high concentrations of fructose (upto 240 mM in blood) and sucrose, a fructose-glucose disaccharide (up to 1.47 mM in blood at

30 min) (fig. S7), in anoxic tissues suggested thatthese sugars might fuel metabolism under hypoxicconditions. Fructose enters glycolytic metabolismafter phosphorylation by ketohexokinase (KHK)and is converted to fructose-1-phosphate (F1P).Fructolysis is prominent in the kidney, whichexpresses high levels of both the more fructose-selective KHK-C isoform and the less-efficientKHK-A isoform (17–20). Consistently, we detectedhigh levels of F1P in the kidney, which were un-altered after anoxia in both species (Fig. 2D).However, F1P was undetectable in normoxic brainsbut appeared in significant amounts only inanoxic naked mole-rat brains, indicating a switchto fructose metabolism (Fig. 2D). Surprisingly,naked mole-rats were hypoglycemic comparedwith mice (mean blood glucose 3.49 ± 0.1 versus6.66 ± 0.3 mM in mice) (fig. S8A) (21), but duringanoxia, naked mole-rat glucose levels did notshow consistent changes divergent from those inthe mouse (fig. S8). Furthermore, although therewere some differences in glycogen stores be-tween the two species, these were relatively smalland not consistent across all tissues (fig. S8).Fructose can enter cells via GLUT2 and GLUT5,which belong to the SLC2A transporter family(17, 22). The GLUT5 (SLC2A5) protein is a highlyselective fructose transporter (18) predominantlyexpressed in the mouse intestine and kidney buthardly present in the brain and heart (17). Usingquantitative real-time polymerase chain reaction(qPCR), we found that naked mole-rat GLUT5mRNA (Slc2a5) (fig. S9A) was expressed at highlevels (>10-fold higher than mouse) in all exam-ined tissues, including the brain, heart, liver, andlung (Fig. 2E). As analyzed with Western blot-ting, GLUT5 protein levels were higher in nakedmole-rat heart and brain tissue compared withmouse, and levels broadly reflected mRNA levels(Fig. 2F and fig. S9C). Thus, naked mole-rat brainand cardiac tissue likely take up fructose forglycolytic metabolism. Consistently, both KHKisoforms were markedly up-regulated in nakedmole-rat heart, brain, and liver tissue comparedwith the same tissues in mice (Fig. 2G and fig. S9B).Brain tissue from naked mole-rats shows apronounced, intrinsic tolerance to anoxia (19).We thus tested whether naked mole-rat brainscan function by using fructose-fueled glycolyticmetabolism. We measured field excitatory post-synaptic potentials (fEPSPs) in hippocampal slicesfrom mouse and naked mole-rat hippocampi(n = 3 animals per species) before and 60 minafter replacement of 10 mM glucose in the bufferwith 10 mM fructose (normoxic conditions). Withfructose as the sole available sugar, fEPSP ampli-tude declined steadily but at different rates inmouse and naked mole-rat slices (Fig. 3A). Inmice, fEPSPs were almost undetectable 60 minafter the glucose-to-fructose switch, but fEPSPamplitudes in naked mole-rat slices had stabi-lized to ~33% of control values. After slices werereperfused with glucose-containing buffer, meanfEPSP amplitudes returned to control levels innaked mole-rat slices but only partially recoveredin mouse slices [two-way analysis of variance(ANOVA), P < 0.05] (Fig. 3A). We also examinedwhether fructose could be used to fuel the iso-lated beating heart. Naked mole-rat or mousehearts were perfused with Krebs-Henseleit buffercontaining glucose that was then switched tofructose for two periods of 60 min each. TheLVDP of the naked mole-rat hearts remainedstable during both fructose switches. However,in the mouse heart, LVDP was reduced duringboth fructose exposures and differed signifi-cantly from that of naked mole-rat hearts during